Heparin has been used as an effective antithrombotic drug for about fifty years. However, heparin has several side effects associated with its use, such as bleeding and heparin-induced thrombocytopenia. As a result, efforts have been made to develop better antithrombotic agents that do not exhibit such effects. It is further desirable to provide an antithrombic drug which can be administrated orally and is therefore stable in the patient's digestive system.
One approach has been to prepare low molecular weight compounds from heparin. U.S. Pat. No. 4,401,758 discloses oligosaccharides having no more than eight saccharidic moieties possessing anti-Xa activity. The above oligosaccharides are prepared by the depolymerization of heparinic material with nitrous acid. The oligosaccharides so produced are a mixture oligosaccharides, including those having six or fewer saccharides. U.S. Pat. No. 4,777,161 discloses a similar compound comprising a pentasaccharide prepared from alcoholic fractionation of heparinic material.
A second approach is the sulfation of polysaccharides. A sulfated pentasaccharide that binds to AT-III is disclosed by Sinay et al, "Total Synthesis of a Heparin Pentasaccharide Fragment having high Affinity for Antithrombin III," Carbohydrate Research, 132 (1984) C514 C9. A sulfated pentasaccharide prepared from D-glucose and D-glucosamine is disclosed by Choay et al, "Structure-Activity Relationship in Heparin: A Synthetic Pentasaccharide with high Affinity for Antithrombin III and Eliciting high Anti-Factor Xa Activity," Biochemical and Biophysical Research Communications, 116, No. 2, (1983) 492-499. Choay found that while the tetrasaccharide is ineffective in binding antithrombin III, the pentasaccharide is effective. C. R. Ricketts discloses dextran sulfate polysaccharides in "Dextran Sulfate-A Synthetic Analogue of Heparin," Biochem J, 51 (1952) 129, having heparin-like activity.
A third approach is to synthesize antithrombotic substances from lactobionic acid and a diamine. Klauser et al, "Biochemical Studies on Sulfated Lactobionic Acid Amides," Seminars in Thrombosis and Hemostasis, 17 (1991) supp. 1, 118, discloses sulfated lactobionic acid amides having antithrombic properties. The amides so prepared are single chemical entities without heterogeneity in composition or molecular weight, unlike heparin and its derivatives which are a mixture of compositions and molecular weights. Such a lactobionic compound may be attacked in the digestive system by lactase, when orally administered.
The above references fail to disclose the present sulfated cellobionic acid amides and sulfated maltobionic acid amides having anticoagulant properties, suitable for oral administration, and the method of preparing such amides.